The ATR inhibitor elimusertib exhibits anti-lymphoma activity and synergizes with the PI3K inhibitor copanlisib

ATR 抑制剂 elimusertib 具有抗淋巴瘤活性,并与 PI3K 抑制剂 copanlisib 产生协同作用

阅读:3
作者:Giulio Sartori, Chiara Tarantelli, Filippo Spriano, Eugenio Gaudio, Luciano Cascione, Michele Mascia, Marilia Barreca, Alberto J Arribas, Luca Licenziato, Gaetanina Golino, Adele Ferragamo, Stefano Pileri, Giovanna Damia, Emanuele Zucca, Anastasios Stathis, Oliver Politz, Antje M Wengner, Francesco

Abstract

The DNA damage response (DDR) is the cellular process of preserving an intact genome and is often deregulated in lymphoma cells. The ataxia telangiectasia and Rad3-related (ATR) kinase is a crucial factor of DDR in the response to DNA single-strand breaks. ATR inhibitors are agents that have shown considerable clinical potential in this context. We characterized the activity of the ATR inhibitor elimusertib (BAY 1895344) in a large panel of lymphoma cell lines. Furthermore, we evaluated its activity combined with the clinically approved PI3K inhibitor copanlisib in vitro and in vivo. Elimusertib exhibits potent anti-tumour activity across various lymphoma subtypes, which is associated with the expression of genes related to replication stress, cell cycle regulation and, as also sustained by CRISPR Cas9 experiments, CDKN2A loss. In several tumour models, elimusertib demonstrated widespread anti-tumour activity stronger than ceralasertib, another ATR inhibitor. This activity is present in both DDR-proficient and DDR-deficient lymphoma models. Furthermore, a combination of ATR and PI3K inhibition by treatment with elimusertib and copanlisib has in vitro and in vivo anti-tumour activity, providing a potential new treatment option for lymphoma patients.

特别声明

1、本文转载旨在传播信息,不代表本网站观点,亦不对其内容的真实性承担责任。

2、其他媒体、网站或个人若从本网站转载使用,必须保留本网站注明的“来源”,并自行承担包括版权在内的相关法律责任。

3、如作者不希望本文被转载,或需洽谈转载稿费等事宜,请及时与本网站联系。

4、此外,如需投稿,也可通过邮箱info@biocloudy.com与我们取得联系。